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Risk Reduction for Alzheimer's Disease (rrAD)

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ClinicalTrials.gov Identifier: NCT02913664
Recruitment Status : Recruiting
First Posted : September 26, 2016
Last Update Posted : January 11, 2018
Sponsor:
Collaborators:
Texas Health Resources
University of Kansas Medical Center
Washington University School of Medicine
Pennington Biomedical Research Center
Michigan State University
Information provided by (Responsible Party):
Rong Zhang, University of Texas Southwestern Medical Center

Brief Summary:
Physical inactivity, high blood pressure and dyslipidemia are risk factors for Alzheimer's disease (AD) and vascular dementia. Importantly, these risk factors are modifiable with lifestyle changes, pharmacological treatment, or both. The rrAD study will determine effects of aerobic exercise training and intensive vascular risk reduction on cognitive performance in older adults who have high risk for AD.

Condition or disease Intervention/treatment Phase
Cognitively Normal Older Adults Hypertension Subjective Cognitive Decline Family History of Alzheimer's Disease Drug: Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine) Behavioral: Aerobic Exercise Training Other: Usual Care Behavioral: Stretching Exercise Drug: Atorvastatin Phase 2 Phase 3

Detailed Description:
Numerous lines of evidence suggest that interventions that confer therapeutic benefits for cardiovascular health are also associated with improvements in, or preservation of, cognitive function. Many believe "What's good for the heart is good for the brain." However, stronge scientific evidence is needed to prove this hypothesis. The rrAD study is a 4-arm, multicenter, randomized trial to assess the effects of aerobic exercise training and intensive pharmacological reduction of vascular risk factors on cognitive performance in older adults who have high risk for AD, that is, those who have high blood pressure, family history of dementia or subjective memory complaints. Furthermore, rrAD will examine effects of exercise and vascular risk reduction on brain volume, perfusion, and neural network connectivity using magnetic resonance imaging (MRI).

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 640 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Exercise and Intensive Vascular Risk Reduction in Preventing Dementia
Study Start Date : September 2016
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : September 2022


Arm Intervention/treatment
Experimental: Aerobic Exercise (Ex)
Aerobic exercise training; blood and cholesterol management will be standard-care by participant's regular doctor.
Behavioral: Aerobic Exercise Training
Participants will take part in a supervised, moderate to vigorous aerobic exercise training program for approximately 24 months. This program consists of exercising 3 times per week for about 30 minutes per session at the beginning, and will increase to 4-5 times per week, 40-50 minutes per session over a period of 4-5 months. Exercise frequency, intensity and duration will be maintained at this level during the rest of the study period.

Other: Usual Care
Participants will follow their regular doctor's recommendations for blood pressure and lipid control.

Experimental: Intensive Reduction of Vascular Risk Factors (IRVR)
Lowering SBP < 130 mmHg, administration of atorvastatin 80 mg daily, and stretching exercise.
Drug: Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine)

Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine) will be used to reduce SBP<130 mmHg; atorvastatin 80 mg daily will be administered to reduce blood lipid level. Additional antihypertensives may be used if needed.

Intensive Reduction of Vascular Risk Factors (IRVR)


Behavioral: Stretching Exercise
Participants will perform home-based stretching exercise 3 times per week, gradually increased to 4-5 times per week over a period of 4-5 months, and maintained at this level during the rest of the study period. They will be encouraged to attend monthly stretching exercise classes, which will be led by study staff or exercise trainers.

Drug: Atorvastatin
Experimental: IRVR+Ex
A combination of IRVR and aerobic exercise training.
Drug: Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine)

Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine) will be used to reduce SBP<130 mmHg; atorvastatin 80 mg daily will be administered to reduce blood lipid level. Additional antihypertensives may be used if needed.

Intensive Reduction of Vascular Risk Factors (IRVR)


Behavioral: Aerobic Exercise Training
Participants will take part in a supervised, moderate to vigorous aerobic exercise training program for approximately 24 months. This program consists of exercising 3 times per week for about 30 minutes per session at the beginning, and will increase to 4-5 times per week, 40-50 minutes per session over a period of 4-5 months. Exercise frequency, intensity and duration will be maintained at this level during the rest of the study period.

Placebo Comparator: Usual Care
Blood and cholesterol management will be standard-care by participant's regular doctor, and stretching exercise.
Other: Usual Care
Participants will follow their regular doctor's recommendations for blood pressure and lipid control.

Behavioral: Stretching Exercise
Participants will perform home-based stretching exercise 3 times per week, gradually increased to 4-5 times per week over a period of 4-5 months, and maintained at this level during the rest of the study period. They will be encouraged to attend monthly stretching exercise classes, which will be led by study staff or exercise trainers.




Primary Outcome Measures :
  1. Change in global neurocognitive function [ Time Frame: 2 Years ]
    Alzheimer's Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite (ADCS-PACC) and NIH Toolbox (NIH-TB) Cognition Battery will be used to assess changes in neurocognitive function. The composite z-score for global cognition will be obtained by conversion of individual test scores to the standardized z-scores, then averaged to obtain a composite score.


Secondary Outcome Measures :
  1. Domain-specific neurocognitive function assessed by using the tests included in the ADCS-PACC and NIH-TB Cognition. [ Time Frame: 2 Years ]
  2. Whole brain and hippocampal volume assessed via Magnetic Resonance Imaging (MRI). [ Time Frame: 2 years ]
  3. Global and regional brain perfusion assessed via Magnetic Resonance Imaging (MRI). [ Time Frame: 2 years ]
  4. Brain white matter hyperintensity (WMH) assessed via Magnetic Resonance Imaging (MRI). [ Time Frame: 2 years ]
  5. Brain white matter microstructural integrity assessed via Magnetic Resonance Imaging (MRI). [ Time Frame: 2 years ]
  6. Brain neural network functional connectivity assessed via functional Magnetic Resonance Imaging (MRI). [ Time Frame: 2 years ]
  7. Patient-reported outcomes (PRO) of mental and physical health and health-related quality of life assessed by using NIH PROMIS. [ Time Frame: 2 years ]
  8. Physical function assessed via the Short Physical Performance Battery (SPPB). [ Time Frame: 2 years ]
  9. Dual task performance assessed via distracted and non-distracted 10 meter walk. [ Time Frame: 2 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   60 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 60-85, all races/ethnicities, and both sexes are eligible.
  2. a) A positive family history of dementia defined as having at least one first-degree relative with a history of AD or other type of dementia,or b) having subjective cognitive decline.
  3. Mini-Mental State Exam (MMSE) ≥ 26 to exclude gross dementia.
  4. Must lead a sedentary lifestyle defined by not having an "active" rating on Rapid Assessment of Physical Activity (RAPA), i.e., score below 6 on RAPA.
  5. a) Individuals treated for HTN with 110 ≤ SBP ≤ 130 mmHg; or b) Individuals with SBP > 130 and SBP < 180 (If an individual, not treated for HTN, has a SBP ≥ 125 mmHg, consider rescreening after 24 hours).
  6. Willingness to be randomized into the treatment groups and ability to return to clinic for follow-up visits over 24 months.
  7. Fluency in English, adequate visual and auditory acuity to allow neuropsychological testing.
  8. Participants must have a regular healthcare provider.
  9. Physical ability to undergo exercise training; able to walk 10 minutes without pain.

Exclusion Criteria:

  1. Clinically documented history of stroke, focal neurological signs or other major cerebrovascular diseases based on clinical judgment or MRI/CT scans such as evidence of infection, infarction or other brain lesions.
  2. Diagnosis of AD or other type of dementia, or significant neurologic diseases such as Parkinson's disease, seizure disorder, multiple sclerosis, history of severe head trauma or normal pressure hydrocephalus.
  3. Evidence of severe major depression (GDS > 12, may be rescreened after 12 weeks or longer if evidence of reactive depression or temporary mood disturbances) or clinically significant psychopathology(e.g. psychosis and schizophrenia); if hospitalized in past year, can be rescreened in 6 months; or presence of a major psychiatric disorder that in the investigator's opinion, could interfere with adherence to research assessments or procedures.
  4. Unstable heart disease based on clinical judgment (e.g., heart attack/cardiac arrest, cardiac bypass procedures within previous 6 months and congestive heart failure),or other severe medical conditions.
  5. History of atrial fibrillation and evidence on ECG with any of the following: active symptoms of persistent palpitation, dizziness, history of syncope, chest pain, dyspnea, orthopnea, shortness of breath at rest, or paroxysmal nocturnal dyspnea within the past 6 months; resting heart rate of < 30 or > 110 bpm; taking class I or III anti-arrhythmic drugs including flecanide, propafenone, dronedarone, sotalol, dofetilide, and amiodarone; or clinical concerns for safely participating in exercise and lowering blood pressure.
  6. Systolic BP equal or greater than 180 mmHg and/or diastolic BP equal or greater than 110 mmHg, may be rescreened in 1 week.
  7. Orthostatic hypotension, defined as the third standing SBP < 100mmHg, may be rescreened after 2 weeks.
  8. History of significant autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, or polymyalgia rheumatic.
  9. Significant history of alcoholism or drug abuse within the last five years.
  10. Uncontrolled diabetes mellitus, defined as hemoglobin A1C > 7.5%, or requiring insulin treatment.
  11. Regularly smoking cigarette within the past year.
  12. Women with a potential for pregnancy, lactation/child bearing (2 year post- menopausal or surgically sterile to be considered not child bearing potential).
  13. Participant enrolled in another investigational drug or device study, either currently or within the past 2 months.
  14. Severe obesity with BMI ≥ 45; clinical judgment should be applied in all cases to assess patient safety and anticipated compliance.
  15. Allergy to angiotensin receptor blockers (ARBs), i.e., drugs that have a suffix "-sartan".
  16. Allergy to other study drugs or their ingredients; for example, clinical history or self-reported allergy or intolerance to atorvastatin.
  17. Abnormal screening laboratory tests (e.g., liver ALT and AST > 3 x ULN, CK > 3 x ULN, GFR < 30 or Hct < 28%); may be rescreened after 2 weeks or longer.
  18. A medical condition likely to limit survival to less than 3 years.
  19. Participant has any condition(s) judged by the study investigator to be medically inappropriate, risky or likely to cause poor study compliance. For example:

    1. Plans to move outside the clinic catchment area in the next 2 years;
    2. Significant concerns about participation in the study from spouse, significant other, or family members;
    3. Lack of support from primary health care provider;
    4. Residence too far from the study clinic site such that transportation is a barrier including persons who require transportation assistance provided by the study clinic funds for screening or randomization visits;
    5. Residence in a nursing home; persons residing in an assisted living or retirement community are eligible if they meet the other criteria.
    6. Other medical, psychiatric, or behavioral factors that, in the judgment of the site PI or clinician, may interfere with study participation or the ability to follow the study Protocol.
    7. Couples or significant partners who live together cannot be enrolled or participate simultaneously in the study.
  20. Lack of approval from participant's regular healthcare providers, i.e. a signed letter of agreement for the participants to be enrolled in rrAD.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02913664


Contacts
Contact: Lauren Braunfeld, BS 214-345-7134 LaurenBraunfeld@TexasHealth.org
Contact: Ann Jacob, BSN 214-345-4665 AnnJacob@TexasHealth.org

Locations
United States, Kansas
University of Kansas Medical Center Research Institute Recruiting
Kansas City, Kansas, United States, 66160
Contact: Angela VanSciver    913-945-5029    avansciver@kumc.edu   
Principal Investigator: Jeffrey Burns, MD         
United States, Louisiana
Pennington Biomedical Research Center Recruiting
Baton Rouge, Louisiana, United States, 70808
Contact: Sara Goff    225-763-0910    sara.goff@pbrc.edu   
Principal Investigator: Jeffrey Keller, PhD         
United States, Missouri
Washington University in St. Louis Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Monica Sewell    314-286-2716    sewellm@wustl.edu   
Principal Investigator: Ellen Binder, MD         
United States, Texas
UT Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: Lauren Braunfeld, BS    214-345-7134    LaurenBraunfeld@texashealth.org   
Contact: Ann Jacob, BSN    214-345-4665    AnnJacob@TexasHealth.org   
Principal Investigator: Rong Zhang, PhD         
Sponsors and Collaborators
University of Texas Southwestern Medical Center
Texas Health Resources
University of Kansas Medical Center
Washington University School of Medicine
Pennington Biomedical Research Center
Michigan State University
Investigators
Principal Investigator: Rong Zhang, PhD UT Southwestern Medical Center
Principal Investigator: Jeffrey Keller, PhD Pennington Biomedical Research Center
Principal Investigator: Jeffrey Burns, MD University of Kansas Medical Center
Principal Investigator: Ellen Binder, MD Washington University School of Medicine
Principal Investigator: Munro Cullum, PhD UT Southwestern
Principal Investigator: Diana Kerwin, MD Texas Health Resources

Additional Information:
Responsible Party: Rong Zhang, Professor of Neurology, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT02913664     History of Changes
Other Study ID Numbers: RZNIA60
First Posted: September 26, 2016    Key Record Dates
Last Update Posted: January 11, 2018
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data from the study will be shared approximately 18-24 months after the primary study publication.

Keywords provided by Rong Zhang, University of Texas Southwestern Medical Center:
Dementia
Alzheimer's Disease
Cognitive Function
Blood Pressure
Cholesterol
Physical Activity
Exercise
Magnetic Resonance Imaging

Additional relevant MeSH terms:
Antihypertensive Agents
Alzheimer Disease
Cognitive Dysfunction
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Atorvastatin Calcium
Angiotensinogen
Amlodipine
Losartan
Calcium Channel Blockers
Angiotensin Receptor Antagonists
Angiotensin II
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Membrane Transport Modulators
Vasodilator Agents
Anti-Arrhythmia Agents
Angiotensin II Type 1 Receptor Blockers